An efficient four-component reaction was developed to take advantage of the reactivity of the 2-aminothiophenecarbonitrile functionality. The Gewald reaction is a very useful and versatile method for condensation of aliphatic aldehyde or ketone or β-dicarbonyl compound with active nitrile and. The Gewald reaction is an organic reaction involving the condensation of a ketone (or aldehyde when R2 = H) with a α-cyanoester in the presence of elemental.
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The versatility of title compounds as a synthetic entry to fused heterocycles such as thieno[3,4-c]thiolactones, thieno[2,3-b]pyrroles, thieno[2,3-d]pyrimidines and thieno[2,3-b]pyridines is highlighted in following chapters. Even though 2-substituted thiazoles are important structures in their own right, further substitution can be easily achieved through published protocols to form 2,4-substituted thiazoles, gewld thiazoles and also 2,4,5-substituted thiazoles .
Initially, the reaction of several nitriles was screened with aldehyde precursor 10 to determine the selectivity between thiophene and thiazole products.
Also, substrate 46lacking an acidic proton, was recovered unchanged from the reaction. These key intermediates were alkylated with rraction alkyl halides to furnish the final derivatives 65 Scheme Scheme 15 Table 9.
Utilization of substituted 2-aminothiophenes and Gewald reaction in the synthesis of condensed heterocycles The substituted 2-aminothiophenes found enormous utility in dye chemistry, modern drug designbiodiagnostics, electronic and optoelectronic devices, conductivity-based sensors, and self-assembled superstructures.
The free amino group allowed the chain elongation and the growth of p-conjugated system to achieve structure with three thiophene units 86 Figure 9 upon its modification via deamination reaction38,39,82, followed by the Gewald reaction.
Thiophenes, Thiophene 1,1-dioxides, and Thiophene 1-oxides. The reaction of corresponding bromomethylated thiophenes 37a-c with thiourea in acetone proceeded thiouronium salts 38a-c in almost quantitative yields. A series of thieno[2,3-d][1,3]oxazinones 65 was synthesized and evaluated in vitro for inhibitory activity toward Human Leukocyte Elastaze HLE. In this case the rfaction, mainly secondary amine diethylamine, morpholineis used in 0.
Her scientific achievements are focused on the synthesis of new heterocyclic compounds. This process represents the advancement of the basic version 4 content 2.
Norris25 and ten years of the last Gewald reaction review26 we felt the time was ripe for a fresh look at this field of heterocyclic chemistry. Particular attention is given to studies published in the previous years. Kemi16, After the dispersion of reagent 17 in ethanol Gewald reaction was performed in QuestTM synthesizer by mixing with the starting compound – a-methylene carbonyl compounds 18 and substrates – sulfur and morpholine. This further shows the need for the rapid and facile formation of 2-substituted thiazole compounds as core building blocks.
Inshe moved to University of SS.
Aminothiophenes 62 were converted to isothiocyanato-thiophenes 63 by the thiophosgene method. Applications of substituted 2-aminothiophenes in drug design, optoelectronics and dyes 4. Depending on the used starting substrates and the reaction conditions three basic versions of the Gewald reaction have been developed16, which were lately enriched by a fourth version.
Gewald reaction – Wikipedia
It was shown that the geald of an alkyl or aryl substituent adjacent to the cyano group leads selectively to the thiazole by blocking the Gewald type mechanism responsible for the formation of the 2-aminothiophene. International Patent No WO As was reported in, the facile one-pot synthesis of polysubstituted thiophenes and thieno[2,3-b]thiophenes was completed through cyclization of a-oxo ketene S,S -acetals.
The reaction reported by authors represents the one-pot synthesis in which the reaction sequence follows the Gewald reaction process. Tetrahedron reachion, 54, Some authors report that the activation of sulfur and the following addition of sulfur on a methylene group is base-promoted, others detail the electrochemical activation of the S8.
Based on these author observations reported a synthesis of the number of analogs of 74 via the Gewald reaction and evaluated for cytotoxic activity against Rifampicin-resistant Reacfion. Pharmazie51, 7.
Chemistry16, geaald Synthesis45, 45— Presented synthetic approach is relevant also for the preparation other biologically active thienopyrimidine structures.
Deprotection of tertbutoxycarbonyl group resulted directly to ring closure of the intermediates isothiocyanatothiophenecarboxylic acids leading directly to 64a,b.
Thiazole formation through a modified Gewald reaction
The synthesis of thiazoles and thiophenes starting from nitriles, via a modified Gewald reaction has been studied for a number of different substrates. Drugs Future27, The chemistry of aminothiophenes has been broadly summarized in in the monograph of R.
Cinnamyl derivatives of thieno[2,3-d]oxazinones 72 Figure 5 inhibits herpes protease processing in HSV-2 infected cells. It was proved, that the rreaction aminothiophene occurs exclusively in the amino form.
The review starts with an extensive introduction that discusses the most multidisciplinary areas of 2-aminothiophene research with inputs from medicine, pharmacology, chemistry, biology, biochemistry, materials science and physics. Polymer,48, Macromolecules40, Mallia 1Lukas Englert 1Gary C.
VolumeIssue 1Reviews and Accountspp. Data of the utilization of 2aminothiophenes in the synthesis of novel type of fused heterocycles and their application are included. Thiophene and its derivatives. Scheme 5 Alkyl aryl ketones and some cycloalkyl ketones which are not reactive under the one-pot modifications version 1 or version 2 give acceptable yields of thiophenes in the two-step procedure Table 3. Circulation83,